To characterize CEBP-altered B-cell acute lymphoblastic leukemia (B-ALL) across pediatric, adolescent and young adult, and adult patients using whole-transcriptome sequencing, and compare the resulting profiles with previously reported subtypes.
Approach:
Cohort and analysis: Whole-transcriptome sequencing was used to analyze 24 CEBP-altered B-ALL cases from an Australian cohort spanning pediatric, AYA, and adult patients.
Fusion detection: The RIGHT workflow and analysis of regions flanking CEBP genes were applied to identify IGH and CEBP rearrangements from RNA sequencing.
Key Findings:
Unbiased transcriptomic analysis separated the 24 cases into two clusters, broadly concordant with the CEBP/ZEB2 and CEBPalt subtypes reported by Kim et al.
Cluster A was associated with ZEB2 p.H1038R and NRAS mutations, more frequent CDKN2A deletions, and CEBPE rearrangements.
Cluster B was characterized by FLT3 mutations, frequent IKZF1 deletion, a higher burden of karyotypic gains and losses, and CEBPD rearrangements.
The clusters differed in developmental-state signatures: Cluster B was enriched for pre-B I cells, while Cluster A contained more pre-B II Small or Immature B cells.
CEBP rearrangements were detected in 19 of 24 cases using transcriptomic sequencing and the described analytical framework; rearrangements were associated with increased expression of the affected CEBP gene.
Both clusters included pediatric, AYA, and adult cases, with no significant age-group or sex differences within this non-consecutive cohort.
Interpretation:
The authors report that whole-transcriptome sequencing, when analyzed with an IGH-sensitive framework, can distinguish two CEBP-altered B-ALL profiles. Their findings support the view that IGH::CEBPE alone incompletely represents the biology and that cooperating lesions and developmental programs distinguish the groups.
Limitations:
The cohort was non-consecutive and comprised 24 cases.
The authors state that larger independent cohorts are needed to determine whether differences from previously reported age and sex associations reflect cohort composition or genuine variation.
Functional studies are needed to establish the relationship between developmental state and the different cooperating pathways.
Whole-transcriptome sequencing may not identify noncoding regulatory alterations or cryptic structural variants that can be detected by comprehensive genomic methods.
Conclusion:
The study independently supports two transcriptomic profiles within CEBP-altered B-ALL across age groups. The supplied article context ends before its final sentence.
